Targeting breast cancer stem cells

 描述(由申请人提供)：肿瘤细胞的异质性对有效的癌症治疗方法的发展提出了一个巨大的挑战。除了由突变和克隆选择引起的遗传异质性已得到充分研究外，越来越多的证据表明，表观遗传异质性在调节治疗耐药中发挥着基础性作用。调节细胞分化的表观遗传机制在肿瘤内产生层级组织的细胞克隆。在这些层次结构的顶端是癌症干细胞(CSCs)，它们驱动肿瘤的生长和转移。CSCs具有表型可塑性，能够在间充质状态和上皮样状态之间转换，这一过程受肿瘤微环境的调节。CSCs也表现出对细胞毒剂和放射治疗的内在耐药性，也可能对针对肿瘤群体的分子靶向治疗产生耐药性。CSC的异质性、可塑性和治疗耐药性对于开发有效的癌症治疗方法具有深远的意义。 在过去的十年中，我们的实验室已经在乳腺癌以及其他肿瘤类型中确定了CSCs的标志物，并开发了有助于分离和鉴定这些细胞的体外和小鼠模型。我们已经确定了一些调节这些细胞的内在和微环境驱动的途径，促进了CSC靶向药物的开发，其中一些现在已经进入临床试验。我们建议通过应用单细胞基因组和蛋白质组技术来扩展这些研究，以在单细胞分辨率下表征CSC的异质性。我们将开发新的技术来捕获和分子询问分子注释的PDX模型中的循环CSCs，以及在原始患者血液样本中。这些技术将有助于更准确地选择靶向CSCs的药物，并有助于对CTC靶向临床试验患者的治疗效果进行实时评估。CSCs的成功靶向有可能显著改善乳腺癌和其他恶性肿瘤患者的预后。

 DESCRIPTION (provided by applicant): Tumor cellular heterogeneity presents a formidable challenge to the development of effective cancer therapeutics. In addition to well-studied genetic heterogeneity resulting from mutation and clonal selection, there is mounting evidence for a fundamental role of epigenetic heterogeneity in mediating therapeutic resistance. Epigenetic mechanisms regulating cellular differentiation generate hierarchically organized cellular clones within tumors. At the apex of these hierarchies are cancer stem cells (CSCs) which drive tumor growth and metastasis. CSCs are endowed with phenotypic plasticity enabling them to transition between mesenchymal and epithelial-like states, processes regulated by the tumor microenvironment. CSCs also display intrinsic resistance to cytotoxic agents and radiation therapy and also may be resistant to molecularly targeted therapies aimed at bulk tumor populations. CSC heterogeneity, plasticity, and therapeutic resistance have profound implications for development of effective cancer therapies. Over the past decade, our laboratory has identified markers for CSCs in breast cancer, as well as other tumor types and developed in vitro and mouse models that have facilitated isolation and characterization of these cells. We have identified a number of cell intrinsic and microenvironmentally driven pathways that regulate these cells facilitating development of CSC-targeting drugs, a number of which have now entered clinical trials. We propose to extend these studies by applying single-cell genomic and proteomic technologies to characterize CSC heterogeneity at single-cell resolution. We will develop novel technologies to capture and molecularly interrogate circulating CSCs in molecularly annotated PDX models, as well as in primary patient blood samples. These technologies will facilitate more precise selection of agents to target CSCs, as well as facilitating real time assessment of therapeutic efficacy for patients on CTC targeting clinical trials. The successful targeting of CSCs has the potential to significantly improve the outcomes of patients with breast cancer, as well as other malignancies.